The complex nature of the sperm DNA damage process

tau.amegroups.com © Translational Andrology and Urology. All rights reserved. Dr. Menezo and colleagues (1), in their commentary regarding the practice recommendations for sperm DNA fragmentation (SDF) testing based on clinical scenarios by Agarwal et al. (2), pointed to the importance of distinguishing between SDF and sperm nucleus decondensation (SND) as these are independent processes. The authors reasoned that while the oocyte has a limited capacity to repair DNA strand breaks, it is poorly equipped to repair nucleus decondensation. They go further by listing conditions more likely to be associated with one (e.g., lifestyle factors and SDF) or the other (e.g., IVF/ICSI failure due to early embryo arrest and nucleus decondensation) and the tests best suited to measure SND. In our reply, we provide a brief overview of the last stage of spermatogenesis to help readers comprehend the problem of SND and DNA fragmentation. Moreover, we discuss in further detail the differences among the existing tests for sperm DNA damage assessment. Upon meios i s complet ion , the haplo id round spermatids initiate the final differentiation stage termed spermiogenesis. It involves no cell division but rather a complex series of cytological changes leading to the formation of spermatozoa (3). In humans, maturation of round spermatids to spermatozoa is characterized by four main events, i.e., (I) position of the nucleus in an eccentric location and condensation of the nuclear DNA (chromatin compaction) that results in nuclear size reduction; (II) formation of the acrosome from the Golgi complex; (III) tail formation from a pair of centrioles lying adjacent to the Golgi complex and the aggregation of mitochondria; (IV) cytoplasm phagocytosis by Sertoli cells (4). The final result is the production of highly specialized cells with fully compacted chromatin. As mentioned above, histone–protamine transition under normal conditions results in a greater compaction of the sperm DNA molecule than that observed in somatic cells. During this transition, the DNA molecule would have been subjected to a forced twisting of the DNA molecule hadn’t controlled DNA nicking taken place (5). This structural DNA nicking necessary for histone-to-protamine transition seems to be facilitated by topoisomerase II. Hence, any mechanism affecting the process of protamination can result in SND. When sperm maturation is completed, checkpointlike mechanisms may trigger abortive apoptosis of such defective sperm, but the phenomenon is not universal, and sperm with abnormal chromatin compaction can be released in the ejaculate (5). Therefore, SND refers to defects in chromatin compaction (e.g., protamine mispackage via defective DNA-protein crosslinking), which is intrinsically associated with the later stage of spermatogenesis. On the contrary, SDF specifically refers to the breaks occurring at the DNA strands, and they are termed singlestrand (ss) or double-strand (ds) breaks (5,6). SDF often results from oxidative stress in the male reproductive tract (5,6). Excessive reactive oxygen species (ROS) can be generated in the epithelial cells of epididymis under physicochemical stressors such as high temperature and environmental conditions. Activated leukocytes and defective sperm can also release large quantities of ROS (5). As a consequence, redox processes using various pathways, including hydroxyl radical, nitric oxide, and activation of sperm caspases and endonucleases, affect not only the sperm Editorial